18-lower alkyl pregnanes and derivatives



United States Patent Office 3,402,173 Patented Sept. 17, 1968 3,402,17318-LOWER ALKYL PREGNANES AND DERIVATIVES John A. Edwards, Palo Alto,Calif., assignor to Syntex Corporation, Panama, Panama, a corporation ofPanama No Drawing. Continuation-impart of application Ser. No. 441,297,Mar. 19, 1965. This application Feb. 18, 1966, Ser. No. 528,398

24 Claims. (Cl. 260-23955) This application is a c-ontinuation-in-partof United States application Ser. No. 441,297, filed Mar. 19, 1965, nowabandoned.

The present invention relates to a novel process for the preparation of18-lower alkyl-ZO-hydroxy-pregnanes, 18-loweralkyl-20-hydroxy-l9-norpregnanes and derivatives thereof unsaturated inthe ring nucleus and novel intermediates thereof.

The process of the present invention is illustrated diagrammatically asfollows using, for the sake of simplicity, only the C and D rings of thesteroid nucleus.

In the above formulas, R represents a lower alkyl radical containingfrom 1 to 3 carbon atoms such as methyl, ethyl, propyl, and isopropyl, Xis chloride, bromide or iodide, and Z represents a single bond or adouble bond between carbon-9 and carbon-11.

In carrying out the above-illustrated process, the steroid startingmaterial I is reacted with a molar excess, preferably from about 10 molsto about 60 mols, more preferably about 10 to 40 mols, of a lower alkylmagnesium halide per mol of steroid starting material in a suitablesolvent such as the aromatic hydrocarbons, for example, benzene,toluene, xylene, or the like, either alone or in admixture with lesseramounts of inert organic solvents such as dioxane, tetrahydrofuran, orthe like, at a temperature ranging from about 60 C. to about 150 C., andpreferably at the reflux temperature of the solvent employed, for fromabout 24 hours to about 72 hours or longer depending upon temperatureand concentration or reactants, thus giving the 18-alkyl-18-keto steroid(11). Suitable alkyl magnesium halides include the alkyl magnesiumbromides, chlorides, and iodides, preferably the chlorides, wherein saidalkyl contains from 1 to 3 carbon atoms such as ethyl, propyl, methyl,or isopropyl.

The novel 18-lower alkyl-l8-one intermediates (II) can be directlyconverted to the 18-alkyl-18-unoxygenated steroid (III) by Wolff-Kishnerreduction, e.g., by refluxing in a lower alkylene glycol, such asethylene glycol, propylene glycol, diethylene glycol, or the like, withhydrazine hydrate, followed by the addition of potassium hydroxide andfurther refluxing to give a total time of from about 4 to about 8 hours,or by reaction with hydrazine dihydrochloride in the manner described byNagata et al. in Chemistry and Industry (London), page 1194 (1964).

Reduction of the 18-lower alkyl-18-one steroid (II) is preferablycarried out by the method diagrammatically illustrated as followsshowing only the C and D rings wherein R and Z are as defined above.

In practicing the above-illustrated method, the 18-alkyl 18-one steroid(II) is treated with an excess of hydrazine hydrate in an alcohol orglycol solvent such as ethanol, ethylene glycol, triethylene glycol andthe like, at an elevated temperature, preferably under reflux or aboutC. or higher, for a time suflicient, generally about 5 hours or more, toobtain the hydrazone (IIA). Preferably, the hydrazone (HA) is obtainedby reacting the steroid (II) with an excess of hydrazine hydrate, e.g.,about 20 to about 40 molar equivalents in a lower alkylene glycol suchas tri-ethylene glycol in the presence of about 5 to about 10 molarequivalents, preferably about 7 molar equivalents of a strong acid suchas hydrochloric acid or alternatively, hydrazine dihydrochloride,para-toluenesulfonic acid, or the like.

The hydrazine steroid (HA) is then converted into the18-alkyl-20/3-hydroxy steroid (III) by treatment with a strong base.Preferably, this reaction is accomplished by adding a solution of thehydrazone (IIA) in a solvent such as the lower alkylene glycols, e.g.diethylene glycol, to a solution of a strong base in an organic solventmedium while maintaining the temperature of the latter solution at about215 to 240 C., preferably 225 C. The organic solvent medium should havea relatively high boiling point and should be one in which the strongbase, e.g. sodium or potassium hydroxide, is soluble such as the loweralkylene glycols, preferably diethylene glycol. The concentration ofbase in the organic solvent medium may suitably be about 1 to 10%,preferably 3 to 5%. Optionally, in addition to the strong base, theremay be present in the organic solvent medium a small amount, eg about 1to 10%, of hydrazine hydrate. The reaction time is of the order of 2hours or less to 7 hours or more, generally about 5 hours depending uponthe temperature and concentration of reactants. The reaction ispreferably conducted under an inert atmosphere such as nitrogen. Thisreaction may also be accomplished by treating the hydrazone (IIA) withpotassium t-butoxide in a solvent medium of, for example, anhydrousdimethylsulfoxide, toluene, and the like at room temperature or above inthe manner described by Cran et al. in the Journal of the AmericanChemical Society, 84, 17341735 (1962) and Grundon et al. in the Journalof the Chemical Society (London), pp. 1855-1858 (1963).

Included among the starting materials I in the aboveillustrated processare the A -pregnene-3/3,20}8-diol-18-oic 3 4 acid 18,20-lactones and3-esters thereof represented by The starting material I can also be a3-cycloalkylenethe general formula: dioxy-A -pregnadien-ZOfl-ol-l8-oicacid 18,20-1actone,

CHa e.g., the 3-cycloethylenedioxy compound represented by the followingformula: O-CH 5 CH3 0:4;

o-o-H 0=&

lwherein R represents hydrogen or an acyl group, which (E) can beobtained as described in Meystre et al. in Helv. Chim. Acta, 45,13174343 (1962).

The starting material I can also be a 19-nor-Apregnene-3;3,20/3-diol-18-oic acid 18,20-lactone 3-acylate representedby the general formula:

In addition to the preferred starting materials illustrated by FormulasB through E, the following 18,20-lactones 20 of the20-hydroxy-pregnanes, 19-norpregnanes, and derivatives thereofunsaturated in the ring nucleus may be ([3113 used in the process of thepresent invention: 0-0-11 3 fi-acyloxy-ZOfi-hydroxy-5u-pregnan-l8-oicacid 9; W 18,20-lactone,

| 3 8-acyloxy-20/3-hydroxy-1 1-0xo-5a-pregnan-18-oic acid 18,20-lactone,

3p,1 1fl-diacyloxy-ZOB-hydrQXy-Sa-pregnanl8-oic acid 18,20-lactone, 3O3a-acyloxy-ZOB-hydroxy-Sfi-pregnan-18-oic acid 18,20-lactone, 4 03a-acyloxy-20fl-hydroxy-l 1-oXo-5fl-pregnan-l8-0ic acid 18,20-lactone,(C) 3 a,11,9-diacyloxy-ZOfi-hydroxy-SB-pregnan-18-oic wherein R has thesame meaning as set forth hereinabove 3 for Formula B, which can beobtained by first subjecting a A -pregnene-3/3,19-diol-20-one 3-acylate,e.g., the 3-aceacld lszolactone tate, to Jones oxidation conditions,using 8 N chromic acid at about 0 C. to give the correspondingIOB-carboxy ls'olc f lszo'lactone steroid, e.g.,10,8-carboxy-M-pregnen-3 3-ol-20-one-3-ace- 40 h tate, heating thethus-obtained IQB-carboxy steroid in anacld 9' 4 hydrous pyridine in themanner descrcibed by Gardi et al. 3'eth ylenedloxy'lloxo'zofl'hydroxy'A'pregnen'18'mc in Gazz. Chim. Ital., 514-524 (1963), thus giving theacid 9 corresponding 19 no1. A5(10) 2O one cg" 19 nor AWOL3-ethylenedroxy-Z0/3-hydroxy-A -pregnadien-18-010 pregnen-3fi-ol-20-one3-acetate, reducing the keto group acld P- 4 using, for example, sodiumborohydride in an inert or- P Q ganic solvent such as dioxane or thelike, to give the coracld l 4 responding 3,20-diol, e.g., 19-nor-A-pregnene-S/i-Zllfis'ethylfa'nedloxy'l1'oxo'zofi'hydroxy'l9'nor'A'Pregnen' diol 3-acetate, and then using this 3,20-diol 3-acetate asls'olc lszo'lactonea the starting material for the formation of thecorrespond 3'ethylenedloxy'l '0 I 1 ing 18,20-lactone by the methoddescribed in the afore- 0 aclfi a mentioned Meystre et al. article forthe preparation of the 3'ethylene'dloxy'zofl'hydroxy'sx'pregnanlg'olc 1820-lactone corresponding A -compound (see page 1332 of said article),thus giving a 19-nor- -pregnene-3, ,20p 13-ethylene-dioxy-11-0x0-20p-hydroxy-5u-pregnan-18-o1c oic acid18,20-lactone 3-acylate, e.g., the acetate, which can 3 5 gp' fi 1 20 hd 5 then be converted, if desired, to the corresponding free gf z gg i'5132 2 y 3 3-01 by conventional hydrolysis techniques.

The starting material I can also be a 3cycloalkylene-3'ethylenedloxy'zop'hydmxy'sfi'pregnan'ls'olc acld dioxy-l9-nor-A-pregnen-2Ofl-ol-l8-oic acid 18,20-lactone 3 i ggi 20 h d 5 18 or a3-cycloalkylenedioxy-A pregnen-ZOfi-ol-18-oic acid 6 loxy' y roxy'fl'pregnan' 18,20-lactone, e.g., the Ijl-cycloethylenediorry compound 3ig gp' fi 1 20 h d 5 represented by the following formula wherein R ishydroy f l B'acy y foxy" B'Pregnan' gen or methyl: 18-o1c acid18,20-lactone,

3-ethylenedioxy-11-oxo-20fi-hydroxy-Sfi-pregnan-18- oic acid18,20-lactone, 3-ethylenedioxy-1 1-0xo-2OB-hydroxy-A -pregnen-1 8-oicacid 18,20-lactone, 3-ethylenedioxy-1 1a-acetoxy-ZOfl-hydroxy-M-pregnen-18-oic acid 18,20-lactone, 7 3-ethylenedioxy-1 1-oxo-2Ofi-hydroxy-A-pregnenl 8-oic acid 18,20-lactone, 3-ethylenedioxy-l1a-acetoxy-ZOfi-hydroxy-A -pregnen-18- oic acid 18,20-lactone,3-ethylenedioxy-l 1B-acetoxy-ZOli-hydroxy-M-pregnen- 7 1-8-oic acid18,20-lactone,

3-ethylenedioxy-1 1fl-acetoxy-ZOB-hydroxy-M-pregnen- 18-oic acid18,20-lactone, 7 3-ethylenedioxy-1 1-oxo 2Oy3hydroxy-A -pregnenl 8-oicacid 18,20-1actone, I j 3-ethylenedioxy-1 1-oxo-20fi-hydroxy-A-pregnen-18-oic acid 18,20-lactone, v. 3-ethylenedioxy-20fl-hydroxy-Apregnadien-18-0ic acid 18,20-lactone, 3-ethylenedioxy-9, 1 1,8-oxido-20fl-hydroxy-A -pregnenl8-oic acid 18,20-lactone,3-ethylenedioXy-9,1 1 fl-oxido-20fl-hydroxy-A -pregnen- 1 8- oic acid18,20-lactone, 3-etheylenedioxy-20fi,2l-dihydroxy-M-pregnen-l-8-0ic acid18,20-lactone, p 3-ethylenedioxy-20a-hydroxy-A -pregnadien-18-oic acid18,20-lactone, 3-ethylenedioxy-l 1-oxo-2Ofl hydroxy=l9-norA-pregnenl8-oic acid 18,20-lactone, 3-ethylenedioxy-11-oXo-2Ofi-hydroxy-19-noraA -pregnen- 18-oic 18,20-lactone, and thelike.

While the foregoing description of suitable starting materials for thenovel process of the present invention has been with particularreference to the 20,8-hydroxy-l8-oic acid 18,20-lactones, the presentinvention may also use as starting materials the 200z-hYdfOXY-l8-OICacid 1=8,2 0-lactones to prepare the corresponding 18-loweralkyl-20ahydroxy-l8-one steroid which can 'be reduced to thecorresponding l8-lower 'alkyl-20a-hydroxy steroid.

Preparation of the foregoing 18,20-lactones and others suitable asstarting materials for the process of the present invention and startingmaterials therefor may be accomplished, for example, in accordance withthe methods described in the aforementioned Meystre et al. article andU.'S. Patents 3,092,625 and 3,121,080.

The l8-lower alkyl-20-hydroxy-pregnanes, 19-norpregnames andunsaturated'derivatives thereofare valuable intermediates for thepreparation of, for example, the 18-1ower alkyl-pregnane and19-norpregnane derivatives represented by the following formula:

CHa

wherein R represents hydrogen or methyl, R represents a lower alkylgroup containing from 1 to 3 carbon atoms, e.g., methyl, ethyl, propyl,isopropyl, or the like, R represents hydrogen, a hydroxyl group oran'acyloxy group, X represents hydrogen, methyl, or a halogen having anatomic number less than 53, e.g., fluorine, chlorine, or bromine, Z andZ each represent a saturated linkage or a double bond between the carbonatom at the 6- and 7- positions and 9- and ll-positions, respectively,with Z being asaturated linkage when X is hydrogen;

The-acyl and acyloxygroups referred to above and herein-after arepreferably derived from hydrocarbon carboxylic; acids containing-lessthan 12 carbon atoms which may be saturated or-unsaturated, of straight,branched, cyclic or-cylic-aliphatic chain or aromatic, and may besubstituted by functional groups such as hydroxy, alkoxy containing-upto 5 carbon atoms, acyloxy, containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are the acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoacetate, and fl-chloropropionate.

For example, the 18-lower alkyl-ZO-hydroxy steroids describedhereinabove are valuable intermediates for the preparation of 18-alkylsteroids of the type characterized 'by Formula A above. Thus, IS-alkylprogesterones and 19-norprogesterones can be prepared by a reactionscheme which can be illustrated as follows:

(VIII) The above reaction (VI- VII- VIII) is fully described in parentapplication Ser. No. 441,297 referred to hereinabove.

The 18-lower alkyl-ZO-hydroxy steroids (III) prepared by the process ofthe present invention can also be used to prepare 17a-hydroxy and17a-acyloxy-l8-a1kyl-6-unsubstituted progesterones represented byFormula A (R=methyl) hereinabove as illustrated (Formulas 1X throughXVIII) and described in United States application Ser. No. 441,297,filed Mar. 19, 1965.

Another suitable procedure which can be used to pre 'lpare both thel7whydroxy and 17 a-acyloxy-18-alkyl-6-unsubstituted progesterones andtheir 19-nor counterparts represented by Formula A hereinabove can berepresented schematically as follows:

CH3 R R1 CH:

(XXI) In the above formulas, R, R and Z have the same meaning as setforth hereinabove for Formula A, R, represents an acyl group, preferablyacetyl, as defined hereinabove, and R represents an acyloxy group,preferably acetoxy, or cycloethylenedioxy, provided that when Z is adouble bond then R is a cycloalkylenedioxy group and R is methyl andfurther, when R is an acyloxy group, then R is methyl.

In carrying out this reaction scheme, where the starting material XIX isan 18-alkyl-A -pregnene-3p,ZOB-diol 3- acylate or the correspondingl9-nor-A -compound, e.g., 18-methyl-A -pregnene-3fl-20 3-diol 3-acetate(XIX; R and R =methyl, R' =acetoxy), obtainable by selective acylationof the corresponding 3,20-diol using glacial acetic acid at steam-bathtemperature, it is subjected to Jones oxidation to give thecorresponding -ketone (XX), e.g., 18-methyl-A -pregnen-3fl-ol-20-one3-acetate (XX; R and R =methyl, R =acetoxy) Where the starting materialis a 3-cycloalkylenedioxy- 18-alkyl-l9-nor-A -pregnen-20fi-ol, e.g.,3-cycloethylenedioxy-1S-methyl-l9-nor-A -pregnen-20B-ol (XIX; R=hydrogenR =methyl, R =cycloethylenedioxy), it will be oxidized to thecorresponding 20-keto steroid using chromium trioxide in pyridine or thelike, preferably at room temperature overnight, thus giving, forexample, 3-cycloethylene dioxy-l8-methyl-l9-nor-A -pregnen-20-one (XX;R=hydrogen, R =methyl, R' '=cycloethylenedioxy).

Where the starting material is a 3-cycloalkylenedioxy- 18-loweralkyl-A-pregnen-20 8-01, e.g., 3-cycloethylenedioxy-18-methyl-A -pregnen-20B-olor a 3-cycloalkylenedioxy-l8-loweralkyl-A -pregnadiene-2O 8-ol, e.:g.3-cyc1oalkylenedioxy 18 methyl pregna 5,l9(11) dien-2OB o1 (XIX; R and Rare methyl and Z is a double bond between carbon-9 and carbon-11), itmay be oxidized to the corresponding 20-keto steroid by Jones oxidationor by using chromium trioxide in pyridine or the like affording, forexample, 3 cycloethylenedioxy l8 methyl pregna- 5,9(11)-dien-20-one.

The thus-obtained 20-ones are then reacted with an alkali metal tertiaryalkoxide, such a sodium t-butoxide, potassium t-butoxide, or the like,in the presence of oxygen gas, preferably at a temperature of from about5 C. to about 20 C., for from about minutes to about 2 hours, thusgiving the corresponding Hot-hydroperoxy compound XXI, e.g., 17ahydroperoxy 18 methyl- A -pregnen-3fi-ol-20-one 3-acetate (XXI; R and R=methyl, R =acetoxy), 3-cycloethylenedioxy (XXI; R=hydrogen; R =methyl;R' =cycloethylenedioxy), or 3-cycloethylenedioxy 17cc hydroperoxy 18methyl pregna- A -dien-20-one.

By subjecting the thus-formed Not-hydroperoxy steroid to catalytichydrogenation, using a platinum or palladium hydrogenation catalyst,e.g., platinum-on-charcoal, palladium-on-calcium carbonate, or the like,in a lower alkanol, such as methanol, ethanol, or the like, preferablyat room temperature and atmospheric pressure, the correspondingl7a-hydroxy steroid (XXII), e.g., IS-methyl- A-pregnene-3p,17a-diol-2O-one S-acetate (XXII; R and R =methyl; R=acetoxy), 3-cycloethylenedioxy-18- methyl-19-nor-A-pregnen-17a-ol-20-one (XXII, R=hydrogen, R =methyl,R"=cycloethylenedioxy), or 3-cycloethylenedioxy-l8methyl-A -pregnadiene1711-01-20- one (XXII; R and R are methyl, R is cycloethylenedioxy, andZ is a double bond between carbon-9 and car bon-ll) is obtained.

The thus-obtained 18-alkyl-A -pregnene-3fl,17a-diol-20- one 3-acylatescan be acylated in the manner described hereinabove to give thecorresponding 3,17-diacylates which can be selectively hydrolyzed at the3-position in the manner described hereinabove to give the corresponding17-monoacylates, which are then subjected to Oppenauer oxidation to givethe corresponding 18-alkyl-A pregnen-l7a-ol-3,20-dione l7-acylates(XXIII; R and R =methyl, R =acetoxy), which can be hydrolyzed in themanner described hereinabove to give the corresponding free 17a-ols.

Similarly, the 3-cycloalkylenedioxy-18-alkyl-19-nor- A-pregnen-17a-ol-20-ones, the 3-cycloalkylenedioxy-18- alkyl-A-pregnen-17a-ol-20-ones, or the 3-cycloalkylenedioxy-l8-alkyl-A-pregnadiene-17a-ol-2O-ones can be hydrolyzed, using an acid such assulfuric, hydrochloric, p-toluenesulfonic or the like, in an inertorganic solvent such as methanol, acetone, or the like, to give thecorresponding 18-alkyl-l9-nor-A -pregnen-or l8-alkyl-A-pregnen-l7a-ol-3,20-diones or 18-alkyl-A -pregnadienel7a-ol-3,20-diones(XXIII), e.g., l8-methyl-l9-nor-A pregnen-l7a-ol-3,20-dione (XXIII; Rand R =hydrogen, R =methy1), which can then be acylated to give thecorresponding 17-acylates. Alternatively, hydrolysis and esterificationcan be carried out in one step by reacting the 3-cycloalkylenedioxyintermediate with a mixture of acyl anhydride and organic acid in thepresence of an acid catalyst such as p-toluenesulfonic acid or the like.

In lieu of hydrolyzing the steroid XXIII to the corresponding 3-ketosteroid, valuable 18-alkyl corticoids may be prepared by the processoutlined below using, for example, 3-cycloethylenedioxy-18-loweralkyl-A-pregnadien-l7a-ol-20-one as the starting material.

CH3 CHZOH R1 R1 mt: 0:0 mt =0 ---OH --OH 0 [0 o (XXIIA) o (xxna orhononion R1 RI H14) =0 11,4: =0

--OH -OH (XXIID) LA/ (XXIIC) In the above formulas, R is as definedhereinabove and X is fluorine, chlorine or bromine.

18-alkyl corticoids, as represented by Formula XXIID, are valuabletherapeutic agents possessing corticoid activity. These compounds may befurther reacted to introduce additional substituents such as 1, 2, 6 or16-methyl, 6-halo, and so forth to prepare other corticoids of usefultherapeutic properties.

In practicing the process outlined above, the steroid XXIIA, e.g.3-cycloethylenedioxy-l8-methyl-A pregnadiene-17a-ol-20-one, is treatedwith calcium oxide and iodine in, e.g., tetrahydrofuran and methanol toobtain the corresponding ZO-keto-Zl-iodo steroid which when treated withpotassium acetate in, e.g., acetone affords the corresponding20-keto-21-acetoxy steroid. Hydrolysis of the 20-keto-2l-acetoxy steroidby, e.g., potassium bicarbonate in methanol affords the corresponding20-keto-21-ol steroid. The thus-obtained 20-keto-21-hydroxy steroid(XXIIB) upon treatment with acid, e.g., p-toluenesulfonic acid, in aketone such as acetone is hydrolyzed to the 18-loweralkyl-A-pre-gnadiene-17a, 21;8-diol-3,20 dione (XXIIC). The steroid XXIIC maybe transformed by treatment with, eag. N-bromosuccinimide in aqueousdiethylether in the presence of a small amount of perchloric acid intothe corresponding 115-01- 9a-bromo steroid which may be furtherconverted to the corresponding 9,11-epoxide and then treated withhydrogen fluoride or hydrogen chloride to obtain the corresponding1113-01, 9u-fl11010 or 9a-chloro steroid (XXIID) by :known methods; seefor example, Fried et al., J.A.C.S., 79, 1130 (1957) and Fieser andFieser, Steroids, Reinhold Publishing Corp., New York, 682,683 (1959).

The 18-loweralkyl-20-hydroxy steroids (III) prepared by the presentinvention can also be used to prepare the 6-substituted18-alkyl-progester0nes and 19-norprogesterones represented by Formula Ahereinabove as illustrated (Formulas XXIV through XXIX and XXX throughXXXV, respectively) and described in patent application Ser. No. 441,297referred to above.

In order that those skilled in the art can more fully understand thepresent invention, the following examples are set forth. These examplesare given solely for the purpose of illustrating the invention and notas a limitation thereof.

PREPARATION A A solution of 1 gram of A -pregnene-3/3,l9-diol-20-one3-aoetate in 10 cc. of acetone was cooled to C. and then admixed underan inert nitrogen atmosphere, with stirring, with a solution of 8 Nchromic acid, the acid solution being added until its color persisted inthe mixture.

The chromic acid solution was prepared by mixing 26 grams of chromiumtrioxide with 23 cc. of concentrated sulfuric acid and diluting withwater to give 100 cc. of solution.

Following the addition of the chromic acid solution the reaction mixturewas stirred for an additional minutes at 0-5 C., then diluted withwater. The resulting precipitate was collected by filtration, washedwith water and dried under vacuum. Recrystallization from acetone/hexane gave 10B-carboxy-A -pregnen-3B-ol-20-one 3- acetate.

The thus-obtained 10,8-carboxy steroid, when heated at refluxtemperature for 2 hours in 10 cc. of anhydrous pyridine (cf. theabove-mentioned Gardi et al. article), gave 19-norA-pregnen-3/3-ol-2O-one 3-acetate.

A solution of 2 gnams of sodium borohydride in cc. of water was added,with stirring, to a solution of 2 grams of the thus-obtained 19-norsteroid in cc. of dioxane, and the resulting reaction mixture wasallowed to stand at room temperature for 16 hours. Following thisreaction period excess sodium borohydride was decomposed by the additionof acetic acid and the solution was concentrated to a small volume undervacuum and then diluted with water. Next, the product was extracted withethyl acetate, and this extnact was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. Crystallization ofthe resulting solid residue from acetone/ hexane gave 19 nor A5410)pregnene-3fl,20fi-diol 3-acetate.

The thus-obtained 3fi, 20B-diol, when treated according to the proceduregiven at page 1332 of the aforementioned Meystre et al. article, gave19-nor-A -pregnene- 3B,20;8-diol-18-oic acid 18,20-lactone 3-acetate.

10 PREPARATION B I A mixture of 2 grams of l9-nor-progesterone, 30 cc.of 2-cycloethylenedioxybutane '(2-methyl-2-ethyl-1,3-dioxolane) and 70mg. of p-toluenesulfonic acid was refluxed with distillation for 1 hour.Following this reaction period the reaction mixture was cooled to roomtemperature, diluted with water and extracted with ethyl acetate. Thethus-obtained extnact was washed with water until neutral, then driedover anhydrous sodium sulfate and evaporated to dryness. Crystallizationfrom acetone/hero ane gave 3-cy'cloethylenedioxy-1 9-nor-A-pregnen-20-one.

Reduction of the 20-keto group in the thus-obtained S-cycloethylenedioxysteroid, using sodium borohydride in dioxalne in the manner described inthe preceding preparation, gave 3-cycloethylenedioxy 1 9 nor-A-pregnen-ZO/i-ol.

By using this 2013-01 as the starting material for the lactone-formingprocedure of the aforementioned Meystre et al. article,3-cycloethylenedioxy-l9nor-A -pre gnen-18- oic acid 18,20-lactone'wasobtained.

PREPARATION C A mixture of 1.0 grain of chromium trio-xide, 2.0 grams ofsilver chromatc, 10 ml. of water and 10 ml. of pyridine was stirred forone hour and cooled to 0 C. To this mixture there was added 1.1 grams of3-cycloethylenedioxy- 18-iodo-18,20-oxido-A -pregnadiene in 10 ml. ofpyridine. The resulting mixture was then stirred for about 48 hours at40 C., cooled and treated with ether and dilute sodium chloridesolution. The reaction mixture was then filtered, the organic layerseparated and extracted several times with ether. The extracts werewashed with water, dried, land evaporated under vacuum. The residue waschromatographed on silica gel eluting with benzene/ethyl acetateaffording 3-cycloethylenedioxy-A -pregnadien-18-oic acid 18,20-lact-one.

Example I A solution of 1 gram of M-pregnene-BBQOfl-diol-18- oic acidl8,20- lactone 3-acetate in 200 ml. of toluene was admixed with 40 ml.of a 3 N solution of methylmagnesium chloride in tetrahydrofuran, andthe resulting reaction mixture was refluxed for 48 hours. Following thisreaction period the reaction mixture was cooled to room temperature, icewas added, and the mixture was then diluted with water and ethylacetate. The organic layer was then separated and 'washed several timeswith ethyl acetate, following which it was dried over anhydrous sodiumsulfate and evaporated to dryness. Crystallization of the resultingresidue from acetone/hexane gave 18-methyl-M-pregnene-3,8,20fi-diol-18-one.

This procedure was then repeated in every detail but one, namely, A-pregnene-3fl,20fi-diol-18-oic acid 18,20- lactone 3-acetate wasreplaced by 19-nor-A -pregnene- 313,20B-diol-18-oic acid 18,20-1actoneB-acetate and 3-cy cloethylenedioxy 19 nor-A -pregnen-20fi ol-18-oicacid 18,20-lactone, respectively. In each case, the correspondingl8-methyl-18-one, i.e., 18-methyl-19-nor-A -pregnene-3B,20fl-diol 18one, and 3-cycloethylenedioxy-18- methyl 19 nor-A-pregnen-20/8-ol-18-one, respectively, was obtained.

Similarly, by replacing methylmagnesiurn chloride with ethylmagnesiumchloride and propylmagnesium chloride, respectively, and using the threestenoid starting materials mentioned hereinabove, the corresponding18-ethylland l8-propyl-l8-ones, i.e., 18-ethyl-A -pregnene-33,20;8-diol- 18-one, l8 propy l A pregnene-3/3,20/3-diol-18-one, l8-ethyl 19 nor A pregnene 35,2013 diol l8-one, l8 propyl l9 nor-A-pregnene-3/3,20,3-diol-l8-one, 3 cycloethy-lenedioxy 18 ethyl-l9-nor-A-pregnen-20flol-l8-one, and 3 -cycloethylenedioxy-l8-propyl-l9-nor-Apregnen-ZOfl-ol-lS-one, respectively, were obtained.

A mixture of one gram of 18-methyl-A -pregnene- 3B,20 3-diol-18-one, 120cc. of diethylene glycol and cc. of hydrazine hydrate (99100%) wasrefluxed for 3 hours. Next, 5 grams of potassium hydroxide were addedand, following a temperature rise to 230 C., the resulting reactionmixture was refluxed for an additional 4 hours. Following this reactionperiod the reaction mixture was extracted with methylene dichloride,then washed with an aqueous sodium hydroxide solution and diluted withan aqueous saturated sodium chloride solution. The resulting mixture wasthen dried over anhydrous sodium sulfate and concentrated.Recrystallization from acetone gave 18-methyl-A -pregnene-3,8,2013-di0l.

By repeating this procedure in every detail but one,

namely replacing 18-methyl-A -pregnene-3 9,20,8-diol-l8-.

one with the remaining 18-ones prepared as described in Example Ihereinabove, 18-ethyl-A -pregnene-3B,20fl-diol, 18 prOpyl-A -pregnene35,20fl diol, 18-methyl-19-nor- A -pregnene-3B,20 3-diol, 18-ethyl'l9nor-A -pregnene 35,205 diol, 18 propyl 19 nor-A -pregnene 35,20/3-diol,3-cycloethylenedioxy 18 methyl-19-nor-A pregnen-ZOfl-ol,3-cycloethylenedioxy-l8-ethyl-19-nor-A pregnen-ZOB-ol, and3-cycloethylenedioxy-l8-propyl-19- nor-A -pregnen-20 3-ol, respectively,were obtained.

Example III By repeating the procedure of Example I,3-cycloethylenedioxy-A -pregnadien-20/8-ol-l8-oic acid 18,20-lactone and3-cycloethylenedioxy-A -pregnen-ZOB-ol-l8-oic acid 18,20-lactone wereconverted to the corresponding 3-cycloethylenedioxy 18 methyl-A-pregnadien-ZOfiol- 1 8-one and 3-cycloethylenedioxy-l8-methyl-A-pregnen- 20fl-ol-l8-one.

Example IV A solution of 12.2 grams of 3-cycloethylenedioxy-l8- methyl-A-pregnadien-20B-ol-18-one, 400 ml. of triethylene glycol, 80 ml. of 80%hydrazine hydrate and grams of hydrazine dihydrochloride was heatedunder reflux at 145 C. for 5 hours. The mixture was allowed to cool andthereafter poured into water. The resulting mixture was extracted withethyl acetate. The organic extract was then washed with water, dried,and evaporated under vacuum affording the corresponding 18-methyl-IS-hydrazone-ZOB-hydroxyl steroid.

A solution of 20 ml. of 100% hydrazine hydrate and 200 ml. of diethyleneglycol was distilled, under nitrogen, until the internal temperaturereached 225 C. Ten grams of potassium hydroxide was then addedcautiously and distillation continued, under nitrogen, until thetemperature again reached 225 C. A mixture of 15 grams of theabove-prepared 18-hydrazone and 150 ml. of diethylene glycol was thenadded slowly so that the temperature of the reaction mixture wasmaintained at reflux at 225 C. The resulting solution was then heatedunder reflux in a nitrogen atmosphere for 5 hours, cooled, diluted withwater and the precipitate was collected by filtration, washed with waterand dried in vacuo atfording 3-cycloethylenedioxy 18 methyl-A-pregnadien- 205-01 which may be purified by crystallization frommethanol.

Example V By repeating the procedure of Example IV,3-cycloethylenedioxy-l8-methyl-A -pregnen-20 3-ol was obtained using3-cycloethylenedioxy-18 methyl-A -pregnen-20/8-ol- 18-one as thestarting material.

Example VI A mixture of 28 grams of 3-ethylenedioxy-1lfi-acetoxy-ZOfl-hydroxy-M-pregnen-l8-oic acid 18,20-lactone, 700 ml. of toluene,and 400 ml. of 3 N-methyl magnesium chloride in tetrahydrofuran washeated under reflux for 4 days. The reaction mixture was cooled, pouredonto ice, diluted with water and extracted by ethyl acetate. The organiclayer was washed with water, dried, and evaporated affording3-ethylenedioxy-18 methyl-A -pregnen-11[i,20/3-diol-l8-one.

Example VII By repeating the procedure of Example VI,

3-ethylenedioxy-l 1a-acetoxy-2OB-hydroxy-M-pregnen- 18-oic acid18,20-lactone;

3-ethylenedioxy-9,1 1fl-oxido-20/3-hydroxy-A -pregnen- 18-oic acid18,20-lactone;

3oc,1 1u-diacetoxy-ZOp-hydrQxy-SB-pregnan-18-oic acid 18,20-lactone;

3u-acetoxy-20/3-hydroxy-5fl-preguan-18-oic acid 18,20-lactone;

3 a, 1 1[3-diacetoxy-2OB-hydroxy-SB-pregnan-18-oic acid 18,20-lactone;

3 p, 1 1,B-diacetoxy-ZOfl-hydroxy-5a-pregnanl 8-oic acid 18,20-lactone;

3fi-acetoxy-20fi-hydroxy-Sa-pregnan-18-oic acid 18,20-lactone;

3-ethylenedioxy-20fl-hydroxy-A -pregnadien-18-oic acid 18,20-lactone;

3-ethylenedioxy-1 1-oxo-2Ofi-hydroxy-19-nor-A -pregnen- 18-oic acid18,20-lactone;

3-ethylenedioxy-20,8-hydroxy-A -pregnadien-l8-oic acid 18,20-lactone;and

3-ethylenedioxy-20fl-hydroxy-A -pregnadien-18-oic acid 18,20-lactonefurnished 3-ethylenedioxy-18-methyl-A -pregnen-11a,20fldihydroxy-18-one;

3-ethylenedioxy-18-methyl-9, 1 1fl-oxido-A -pregnen-20flhydroxy-18-one;

l8-methyl-5fi-pregnan-3 a,20 3-dihydroxy-l 8-one;

l8-methyl-5fi-pregnan-3 oc,1 15,20fl-trihydroxy-18-one;

l8-1methyl-5a-pregnan-3/3J1B,20/3-trihydroxy-18-one;

18-methyl-5a-pregnan-3fi,2OB-dihydroxy-18-one;

3 -ethylenedioxy-18-methyl-A -pregnadien-ZOB- hydroxy-18-one;

3-ethylenedioxy-18-methyl-l9-nor-A -pregnen-20fihydroxy-11,18-dione;

3-ethylenedioxy-1S-methyl-A -pregnadien-2Ofi-hydroxy- 18-one; and

3-ethylenedioxy- 1 8-methyl-A -pregnadien-20fl-.

hydroxyl 8 -one, respectively.

By substituting ethyl or n-propyl magnesium chloride, bromide or iodidefor the methyl magnesium chloride employed above, the corresponding18-ethyl-18-one and 18-propy1-l8-one may be prepared.

By repeating the procedure of Example IV, the corresponding hydrazoneand 18-methyl steroid of the aboveprepared 18-methyl-18-one steroidswere obtained.

Example VIII By repeating the procedure of Example I, 3fl-acetoxy-20/3-hydroxy-5a-pregnan-18-oic acid 18,20-lactone and 3-ethylenedioxy 11oxo-20a-hydroxy-M-pregnen-18-oic acid 18,20-lact0ne furnished18-methyl-5a-pregnane- 3,6,20fi-dihydroxy-18-one and3-ethy1enedioxy-l8-methyl- A -pregnene-20a-hydroxy-11,18-dione,respectively.

Using the procedure of Example IV, the thus-prepared l8-one steroidswere transformed into the corresponding 18-methyl steroids.

Example IX To a cooled solution of 4 g. of 3-cycloethylenedioxy-18-methyl-A -pregnadien-17a-ol-20-one in 30 ml. of tetrahydrofuran and18 ml. of methanol is first added in small portions 6 g. of pure calciumoxide and then 6 g. of iodine. Stirring at room temperature is continueduntil the solution becomes a pale yellow. The mixture is then 13 pouredinto ice-water containing 18 ml. of acetic acid and 2 g. of sodiumthiosulfate. After stirring for 15 minutes, the solution is decanted andthe solid collected by filtration to yield3-cycloethylenedioxy-l8-methyl-21- iodo-A -pregnadien-l7a-ol-20-one.This compound is mixed with 80 ml. of acetone and 12 g. of recentlyfused potassium acetate. This mixture is refluxed for 8 hours and-thenconcentrated to a small volume, diluted'with water and extracted withethyl acetate. The ethyl acetate extracts are washed with water, driedover sodium sulfate and concentrated until crystallization occurs. Thesolid is collected and recrystallized from rnethanolzwater to yield 3cycloethylenedioxy l8 methyl 21-acetoxy- 11 -pregnadien-17a-ol-20-one. y

A mixture of l g. of 3-cycloethylenedioxy-1S-methyl- 21 acetoxy Apregnadien 17ot-ol-20-one, 2 g. of chloranil, 15 ml. of ethyl acetateand 5 ml. of acetic acid is refluxed under nitrogen for 96 hours. Themixture is then cooled and washed with cold aqueous sodium hydroxideuntil the washings were colorless. The organic solution is dried oversodium sulfate and the ethyl acetate removed by evaporation. Uponchromatography of the residue on neutral alumina there is obtained3-cycloethylenedioxy 1S-methyI-A Q -pregnadiene-17a,2l-diol-20- onewhich may be further purified by recrystallization from acetonezhexane.

A mixture of 0.5 g. of 3-cycloethylenedioxy-18-rnethyl- A5301)pregnadiene 17a,21 diol 20-one in 30 ml. of acetone and 50 mg. ofp-toluenesulfonic acid is allowed to stand at room temperature forhours. It is then poured into ice water and extracted with ethylacetate. These extracts are washed with water to neutrality, dried oversodium sulfate and evaporated to dryness. The residue is triturated withether to yield 18-methyl-A pregnadiene-17a,21-diol-3,20-dione which isrecrystallized from acetonezhexane which may be converted to thecorresponding A -9a-fluoro-10B-hydroxy steroid by conventionalprocedures, see for example Fried et al., J.A.C.S., 79, 1130 (1957).

Example X A solution of 6 g. of 3-cycloethylenedioxy-l8-methyl- A-pregnadien-[3-ol in 120 ml. of pyridine is added to a mixture of 6 g.of chromic trioxide in 20 ml. of pyridine. The reaction mixture isallowed to stand at room temperature for 15 hours, diluted with ethylacetate and filtered through Celite diatomaceous earth. The filtrate iswashed well with water, dried and evaporated to dryness to yield 3cycloethylenedioxy l8 methyl- A -pregnadien-20-one which may be furtherpurified by recrystallization from acetonezhexane.

What is claimed is:

1. A process for the preparation of an 18-lower alkyl-20-hydroxy-pregnane, 19-norpregnane, and derivatives thereof unsaturatedin the ring nucleus which comprises reacting an 18,20-1actone steroidselected from the group consisting of the 18,20-lactones of theZO-hydroxypregnanes, l9-norpregnanes, and derivatives thereofunsaturated in the ring nucleus with a molar excess of the alkylmagnesium halide R MgX wherein R is lower alkyl containing from 1 to 3carbon atoms and X is selected from the group consisting of bromine,chlorine and iodine, reacting the thus-obtained 18-loweralkyl-20-hydroxy-lS-one steroid with a molar excess of hydrazine hydrateto obtain the corresponding l8-lower alkyl-20- hydroxy-18-hydrazonesteroid, and treating said 18-hydrazone with a strong base to obtain'thecorresponding 18-lower alkyl-20-hydroxy steroid.

2. A process according to claim 1 wherein said 18,20- lactone steroid isreacted with said alkyl magnesium halide in an inert aromatichydrocarbon containing organic solvent medium and said 18-one steroid isreacted with said hydrazine hydrate in the presence of a strong acid ina solvent selected from the group consisting of the lower alkyleneglycols and the lower monohydric 14 alcohols, and said 18-hydrazone istreated with an organic solution of a strong base to obtain said18-lower alkyl-20-hydroxy steroid.

3. A process according to claim 1 which comprises reacting an18,20-lactone selected from the group consisting of the 18,20-lactonesof the ZOB-hydroxy-pregnanes, l9-norpregnanes, and derivatives thereofunsaturated in the ring nucleus with said alkyl magnesium halide in aninert aromatic hydrocarbon containing organic solvent medium to obtainthe corresponding l8-lower alkyl- 20 8-hydroxy-l8-one steroid, reactingand l8-one steroid with said hydrazine hydrate in the presence of astrong acid in a solvent selected from the group consisting of the loweralkylene glycols and the lower monohydric alcohols, and treating said18-hydrazone with an organic solution of a strong base to obtain thecorresponding 18-lower alkyl- ZOB-hydroxy steroid.

4. A process according to claim 1 which comprises reacting an18,20-lactone selected from the group consisting of the 18,20-lactonesof the ZOB-hydroxy-pregnanes, 19-norpregnanes, and derivatives thereofunsaturated in the ring nucleus with from about 10 to 60 mols of saidalkyl magnesium halide per mol of said 18,20-lactone at a temperature offrom 60 to C. in an aromatic hydrocarbon solvent selected from the groupconsisting of toluene, benzene, and xylene to obtain the correspondingl8-lower alkyl-20fi-hydroxy-l8-one steroid, refluxing said 18-onesteroid with about 20 to 40 molar equivalents of said hydrazine hydrateand about 5 to 10 molar equivalents of a strong acid in a lower alkyleneglycol solvent to obtain the corresponding 18-hydrazone steroid,dissolving said 18-hydrazone in a lower alkylene glycol solvent toobtain a solution thereof, and adding said solution to an organicsolution of a strong base selected from thegroup consisting of potassiumhydroxide and sodium hydroxide dissolved in a lower alkylene glycol,said base being present in the amount of about 1 to 10% by weight ofsaid organic solution, while main taining the temperature of saidorganic solution at from about 215 to 240 C.

5. A process according to claim 4 wherein said alkyl magnesium halide isan alkyl magnesium chloride.

6. A process according to claim 4 wherein said 18,20- lactone isrefluxed with from about 10 to 40 mols of said alkyl magnesium halideand said 18-one steroid is refluxed with from about 25m 35 molarequivalents of said hydrazine and about 6 to 8 molar equivalents of astrong acid in a lower ,alkylene glycol, and said base is present in theamount of about 3 to 5% by weight.

7. A process according to claim 1 which comprises refluxing an18,20-lactone selected from the group con sisting of the 18,20-lactonesof the 20/3-hydroxy-pregnanes, l9-norpregnanes, and derivatives thereofunsaturated in the ring nucleus with from about 10 to 40 mols of saidalkyl magnesium halide per mol of said 18,20- lactone in toluene toobtain the corresponding l8-lower alkyl-20B-hydroxy-l8-one steroid,refluxing said l8-one steroid with about 30 molar equivalents of saidhydrazine hydrate and about 7 molar equivalents of a strong acidselected from the group consisting of hydrochloric .acid,para-toluenesulfonic acid and hydrazine dihydrochloride in triethyleneglycol to obtain the corresponding 18-hydrazone steroid, dissolving said18-hydrazone in diethylene glycol to obtain a solution thereof, andadding said solution to an organic solution of a strong base selectedfrom the group consisting of potassium hydroxide and sodium hydroxidedissolved in diethylene glycol, said base being present in the amount ofabout 3 to 5% by weight while maintaining said organic solution at atemperature of about 225 C.

8. A process according to claim 7 wherein said organic solution is underan inert atmosphere.

9. A process according to claim 8 wherein said alkyl magnesium halide isan alkyl magnesium chloride, said 15 strong acid is hydrazinedihydrochloride, said base is potassium hydroxide and said inertatmosphere is nitrogen. 10. A process according to claim 9 wherein saidalkyl is methyl.

11. A compound of the formula:

wherein R is a lower alkyl containing 'from 1 to 3 carbon atoms.

12. A compound of the formula:

wherein R is selected from the group consisting of hydrogen and methyl,R is a lower ,alkyl containing from 1 to 3 carbon atoms, Y is selectedfrom the group consisting of beta hydroxyl and cycloethylenedioxy, Y' isselected from the group consisting of hydrogen, alpha hydroxyl, and betahydroxyl, and Z is selected from the group consisting of a single bondand a double bond between carbon-9 and carbon-ll, provided that Z is asingle bond when Y' is hydroxyl.

13. A compound according to claim 12 wherein Z' is ,a single bond.

14. A compound according to claim 12 wherein Z is a single bond, Y isbeta hydroxyl, R is methyl and Y is hydrogen.

15. A compound according to claim 12 wherein Z is a single bond, Y isbeta hydroxyl, Y is hydrogen, R is methyl and R is methyl.

16. A compound according to claim 12 wherein Z is a single bond and Y iscycloethylenedioxy.

17. A compound according to claim 12 wherein Z' is a single bond, Y iscycloethylenedioxy and R is methyl.

18. A compound according to claim 12 wherein Z is a single bond, Y iscycloethylenedioxy, R is methyl and R is methyl.

19. A compound according to claim 12 wherein Z is a double bond, Y' ishydrogen, Y is cycloethylenedioxy, and R is methyl.

20. A compound according to claim 19 wherein R is methyl.

21. A compound of the formula:

RQIO- --H O=C I R l wherein, R is selected from the group consisting ofhydrogen and methyl, R is a lower alkyl containing from 1 to 3 carbonatoms, and R is selected from the group consisting of alpha and betahydroxy.

22. A compound according to claim 21 wherein R is methyl.

23. A compound according to claim 21 wherein R and R are each methyl andR is beta hydroxy.

24. A compound according to claim 21 wherein R and R are each methyl andR is alpha hydroxy.

References Cited UNITED STATES PATENTS 3,287,378 11/1966 Jegcr et al.260-3973 H. FRENCH, Primary Examiner.

12. A COMPOUND OF THE FORMULA: